The aim of this study was to compare the effects of an inhibitor of sorbitol dehydrogenase (2-hydroxy-methyl-4-(N,N-dimethylsulfamoyl-piperazino)pyrimidine = CP-166,572 = SDI), 200mg/kg bwt/day, versus an inhibitor of aldose reductase (zopolrestat=ARI), 100 mg/kg bwt/day, on tibial motor nerve conduction velocity (MNCV) in rats with streptozotocin (55 mg/kg bwt) diabetes of 14 weeks duration. Plasma glucose levels were 5.5+0.0(SD) mM in control (C) rats versus 24+4.2 mM in diabetics (D) and were unaffected by SDI or ARI. MNCV was 62.6+5.1 m/s in C, 68.0+5.6 in C+SDI (p<0.001 vs C), 50.4+3.4 in D (p<0.0001 vs C), 66.7+5.9 in D+SDI (p<0.0001 vs D), and 59.4+7.4 in D+ARI (p<0.0001 vs D) N=9-12 rats per group). Sciatic nerve sorbitol, myo-inositol, and fructose levels (nmol/g wet wt) were 158+33, 3372+625, and 2116+597 for C, 1434+721 for C, 1434+721 (p<0.0001 vs C), 2827+791, and 999+352 (p<0.0001 vs C) for C+SDI, versus 1763+325, 2160+406, and 11584+2890 for D (p<0.0001 vs C for all 3), 10532+3035 (p<0.0001 vs D), 2049+409, and 2071+753 (p<0.0001 vs D) for D+SDL< and 30+10 (p<0.0001 vs D), 2707+483 (p<0.03 vs D), and 1549+586 (p<0.0001 vs D) for D+ARI. In separate studies in rats with diabetes of 5 week duration, SDI and ARI prevented increased sciatic nerve blood flow in (D) but had no effect in (C). These findings indicate that MNCV and vascular dysfunction in peripheral nerve of acutely diabetic rats are more closely linked to metabolic and redox imbalances associated with increased oxidation of sorbitol to fructose than to reduction of glucose to sorbitol, putative osmotic effects of elevated sorbitol levels, and decreased myo-inositol levels.